1. Field of the Invention
This disclosure is related to the field of locating specific ligand receptors, as well as to the use of such strategy to determine a C-peptide receptor.
2. Description of Related Art
The human body in its functions requires a very delicate balance of chemicals in order to process, transfer, and metabolize. The levels of key metabolites in a human body are only properly maintained within a known physiological range by normal action of body organs. Any repetitive change in the concentration of these known chemicals from these expected ranges is generally a sign of illness.
It has been recognized in a number of areas of medicine that identification of peptide receptors for peptides associated with various illnesses can be useful. It is commonly accepted that tissues becoming resistant to the actions of certain peptides can result in some of the chemical imbalances such as diabetes. Further, certain forms of cancerous tumors show increased numbers of certain peptide receptors. Therefore, the knowledge of peptide receptors can be used to selective target therapies.
Diabetes is a disease characterized by an elevated blood glucose concentration as a result of insufficient (or no) insulin production in the pancreas or, in some cases, by insulin resistance. In effect, the body's blood chemistry is regularly outside normal ranges because the blood glucose concentration is higher than it normally would be. This excess concentration can result in a variety of harms to the human body such as damage to tissues due to the excess glucose concentration. Specifically, excess glucose is commonly known to be harmful to blood vessel walls and can cause problems in blood circulation where such vessels are present. This can include damage to the kidneys, extremities, eyes, nerves, heart, and brain.
Diabetes is generally classified in two categories. Type I diabetes generally results when the pancreas creates little, and often no, insulin. In effect, pancreatic function is dramatically reduced or non-existent to the extent that the body simply cannot function with the amount of insulin available regardless of other factors. Type I diabetes is not totally understood, but does seem to have genetic components and may be connected to infections from certain viruses at certain life stages. It generally begins early in life. There are no known cures for Type I diabetes, and currently the only treatment options are monitoring of blood glucose levels and the use of external insulin sources to maintain blood glucose in a desired range.
Type II diabetes is characterized by either insulin resistance, or by the pancreas not producing sufficient insulin. The direct cause of Type II diabetes, is also currently unknown but it appears that a lack of exercise and excess weight can precipitate the onset of Type II diabetes. Most people with Type II diabetes have lived a good portion of their life without it and had workable pancreatic and insulin function prior to the diagnosis. While Type II diabetes is also generally incurable, it can be controlled through insulin therapy in the same way as Type I diabetes and onset can often be halted and/or reversed through lifestyle changes if detection occurs sufficiently early. Essentially, so long as sufficient insulin production capacity remains and insulin resistance is not too high, a controlled diet can allow the body to function correctly with the naturally occurring insulin that is available with Type II diabetes.
According to the International Diabetes Federation, there are currently 246 million diabetics worldwide and the number is expected to reach 380 million by 2025. In many cases, even chronic diabetes is a very controllable disease so long as the body's functions are correctly monitored and glucose (or insulin) is supplied to the body when appropriate. In effect, processes that are normally regulated automatically by the human body become the subject of external regulation and exogenous insulin administration. The prevalence of Type I diabetes is relatively small and generally comprises only about 5% of those with diabetes. Thus, Type II is the primary source of diabetes concerns and costs.
The number of individuals with Type II diabetes has risen dramatically in recent years. It is believed that a diet of processed food which has, in many cases, replaced a diet of unprocessed food for many households has, at least in part, led to this marked increase in the rise of diabetes. Further, the increase in average human weight, and an increased incidence of obesity, along with a general lack of exercise, are also likely contributing factors. Further, as diabetes is a very survivable disease if monitored and controlled, survivability for diabetics is also increasing resulting in additional numbers.
While both forms of diabetes are controllable, therapeutic treatment has focused on the application of external insulin and glucose. Thus, an individual with diabetes is generally doomed to a future of monitoring and external supply. Thus, while an individual can live out their life quite productively with diabetes, the disease causes significant economic costs, lifestyle changes, and a risk of complications from inaccurate monitoring or control that never goes away. Particularly in the long term, diabetes can lead to complications for the individual, including microvascular complications that can result in decreases to quality of life, and even premature death.
It is understood that a lack of insulin, or even an overabundance of insulin, can create medical problems. Even with good control over insulin levels, there is a much increased risk that medical complications can arise when one is on insulin therapy simply because external control of insulin levels will likely never be as accurate as the body's internal controls (when they work correctly). For example, peripheral vascular disease is common among diabetics and generally will occur in Type I diabetics, to some degree, in virtually all cases over a long enough time period. In a large number of cases, this complication, which decreases blood flow to the extremities, can result in amputation of one or more extremities. Indeed, diabetes is the leading cause of non-traumatic leg amputations in the United States.
The production of insulin by the pancreas actually produces two molecules. These molecules are insulin and C-peptide. C-peptide is a protein chain derived from the insulin precursor. For every molecule of insulin created, a molecule of C-peptide is created. C-peptide is metabolized by an individual's kidney at a much slower rate than insulin is metabolized by the liver, so C-peptide can make a useful marker for determining a body's insulin production, regardless of what may be occurring that results in insulin being supplied to the body.
For many years C-peptide was thought to be biologically inert and to have little relevance in medical science beyond its use as a marker for insulin production. However, recent studies have indicated that C-peptide binds to a variety of tissues, initiates intracellular signaling cascades distinct from insulin, and exerts biological activities that may complement insulin action. Interestingly, C-peptide appears to counteract many of the deleterious effects of excess insulin in several tissues, including kidney and vasculature. This suggests that C-peptide may represent a novel therapeutic for the treatment of some diabetes-associated diseases (complications), such as peripheral vascular disease and diabetic nephropathy.
The presence and use of C-peptide may protect against blood vessel damage and deleterious alterations in blood flow that can occur even with well-controlled diabetes due to occurrences of excess (or insufficient) insulin. Alternatively, microvascular complications, including peripheral vascular disease, diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy, may actually be directly related to the lack of C-peptide, not directly to insulin or blood glucose levels.
Currently treatment for many diabetic-related complications are simply to better control blood glucose levels (that is to avoid the insulin imbalances that are believed to cause them) and eliminate known risk factors, such as smoking. While this can be effective, until external insulin monitoring and supply can become as effective as the body's natural internal processes, maintaining the body in perfect balance with any insulin therapy is not possible. Currently, there is no real pharmaceutical treatment directly acting on the complications resulting from diabetes as pharmaceutical treatments focus on either controlling the insulin levels, or trying to better sensitize the body to insulin.
Treatment with C-peptide agonists may be an important adjuvant therapy in Type I diabetes since even in well controlled Type I diabetes vascular complications are highly likely to eventually occur and that may be because of a lack of C-peptide and not failure to control insulin levels. As type I diabetics lack beta cell function, and therefore are C-peptide deficient as well as being insulin deficient, some diabetic complications may result from insufficient C-peptide and not just inaccurate control of insulin. Current methods of insulin therapy, while replacing the specific need for insulin by the body, do not provide C-peptide and therefore a loss of C-peptide may create, or exacerbate, certain complications resulting from Type I diabetes.
Likewise Type II diabetics, in which there is a high incidence of vascular disease, appear to develop some C-peptide resistance, so treatment with C-peptide sensitizers in addition to insulin sensitizers, could potentially help alleviate diabetic complications for Type H diabetics. Thus, the ability to supply the body of a diabetic with C-peptide therapy, while it may not correct or reduce the underlying insulin production function, may help to reduce complications from either form of diabetes.
While the above indicates that C-peptide replacement treatments can be valuable, in order to produce C-peptide agonists and sensitizers, it is necessary to identify the C-peptide receptor, which has thus far eluded detection. There has been speculation that alpha-enolase is a potential C-peptide receptor. However, this has not been confirmed and those skilled in the art are doubtful as typically enolases are intracellular enzymes and not receptors.